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The implications of the latest competition law and policy developments for the pharmaceutical sector

The European Medicines Agency has released its keenly awaited final report on it adaptive pathways pilot and says it will continue to accept applications for the new drug development concept. Meanwhile, law firm Bristows highlights the hurdles ahead for applicants.

The European Medicines Agency is to continue accepting applications for its much-discussed adaptive "i pathways approach for getting drugs for unmet medical needs to market faster, having now completed and reported1 promising results from its pilot project.

Applicants should bear in mind, however, the hurdles they face in pursuing an adaptive pathways approach, Hilary Jones of law firm Bristows told the Pink Sheet.

Challenges for companies include meeting the EMA's rigorous eligibility criteria, the costs that might be involved in following the pathway, and the need to complete a development plan by way of a post-approval commitment, Jones said.

18 of 62 applications were accepted in the pilot, which the EMA launched in March 2014 to learn which types of development programs are suitable for the adaptive pathways approach. By the end of the two-year pilot, six applications had progressed to receive scientific advice that the EMA offers companies in parallel with health technology assessment (HTA) bodies.

The pilot "highlights the challenge that companies face in meeting the eligibility criteria and the fact that a relatively small number of products are suitable for an adaptive pathways approach," Jones said.

Under the adaptive pathways concept, which the EMA is now fine tuning, medicines would first be authorized earlier on in the development cycle than at present for a very small patient population. Additional evidence would then be gathered over time, resulting in progressive licensing adaptations to extend the product's use to increasingly wider populations. Discussions with HTA bodies, patients and other downstream stakeholders would have to take place early on in the process so as to make sure their demands are also met.

The advantages for the marketing authorization (MA) applicant whose product meets the adaptive pathways criteria "may include earlier access to the market, improved focus of research leading to more efficient use of internal resources, and a higher probability of satisfactory reimbursement post MA grant," said Jones.

However, the Bristows lawyer advises applicants to "bear in mind the fact that they will be bound to complete the development plan by way of a post-approval commitment," since priorities and allocation of resource can change over time.

"In addition, significant resource may be required to design and implement a robust development plan and value proposition/reimbursement strategy," she said. "The feasibility of implementation of the development plan (including the recruitment of patients) is also an important consideration."

She added that companies may also want to consider the impact that an earlier MA in a small population may have on regulatory data protection (RDP) for a product, if RDP is relevant to exclusivity.

In its final report on the pilot, which was published on Aug.3, the EMA says that companies that would like to be considered for adaptive pathways should submit a

proposal to the agency. Applications will be considered within the framework of the parallel EMA-Health Technology Assessment scientific advice procedure.

The agency has also published updated guidance for companies that are considering the adaptive pathways approach2.

Drugs Likely To Make It

According to the EMA's report, drugs that are more likely to be accepted for the adaptive pathways approach are those targeting therapeutic areas where evidence generation is challenging, such as infectious diseases, Alzheimer's disease and rare cancers.

The pilot showed that "adaptive pathways should focus on medicines that can plausibly address an unmet medical need in a defined population, where there is scope to explore feasible data collection plans (randomised controlled trials (RCTs) and registries) based on reliable, dear-cut and actionable endpoints."

It also showed that it was possible to bring the multiple stakeholders "around the same table" to discuss a product development paradigm, i.e., regulators, HTA bodies, healthcare professionals and patients.

In addition, it said agreement between stakeholders could "be reached on a prospective approach to evidence generation across the lifespan of a medicine... with a view to optimising and aligning their requirements as much as possible."

Need for More Stakeholder Involvement

However, not all the relevant stakeholders took part in the pilot.

"The report highlights that to date HTA involvement has been limited and payers have not been involved (although it is recognized that going forward they should be where necessary)," said Jones, a senior associate at Bristows' London, UK office.

"It's worth remembering that use of adaptive pathways does not change the fact that reimbursement is a national decision," she noted. "Controlling prescriptions to the defined patient population may well prove challenging in many/most situations due to the lack of a suitable infrastructure and ethical factors."

The report also highlighted a need for more participation by patients. Patients can help select drug candidates for which quicker access is particularly desirable, provide insights on feasibility and ethical aspects, and support enrolment in trials and registries, it explained.

Strategies Still Needed To Collect Real-World Evidence

Identifying methodologically sound strategies for collecting real-world evidence to support the assessment of both efficacy and effectiveness is also a challenge that needs to be addressed, according to the report.

European pharmaceutical industry federation Efpia, which welcomed the report's statement that adaptive pathways can foster multi-stakeholder dialogue, said the challenge relating to real-world evidence collection was clear3.

Data are not always generated to the same standards, and therefore not comparable, Efpia explained. Moreover, e-health systems are not always compatible between hospitals or countries; patients do not have a

j single, electronic health record that stores data in one place; and data are collected for different purposes, which can't always be linked together, "with the added problem that regulation sometimes stops data transfer between systems."

"There is also an immediate need to agree standards and approaches to use real world evidence in addition to randomised clinical trials," Efpia stated. "Combination therapies, and medicines for children and in multi-morbid elderly patients, are often better studied in real-life than in RCTs."

Key Facts

All applications for the pilot came from the pharmaceutical industry, with SMEs accounting for 23% of the 62 initial applications submitted.

Companies that reported their products had been accepted in the pilot include bluebird bio and Immunocore4.

Applications covered a wide range of therapeutic areas, with oncology amounting to around one third of the total initial submissions. Other therapeutic areas that were highly represented included infectious and respiratory diseases, neurodegenerative diseases, and hereditary genetic disorders.

Some of the applications accepted in the pilot failed to progress beyond the initial discussions because the subsequent scientific advice on more detailed protocols cast doubt on the feasibility and methodological robustness of the development plan, the report said.

Reasons for the 44 applications that failed to get accepted in the pilot included:

development programs did not afford scope for expansion and iteration;

some proposals were for areas without unmet need; and

late-stage development programs allowed no changes to the plan.

Next Steps

Adaptive pathways burst on the scene a few years ago when the EMA announced it would consider applications for the approach and explore how to adopt it. Since then, it has been the subject of extensive debate in scientific publications and at conferences5.

The EMA plans to organize a workshop on the topic in December to gather more views on the concept. EFPIA also plans to carry out its own evaluation of its members' experience prior to the workshop.

"Whilst it's clear that adaptive pathways is still a concept in development, with input required from many stakeholders there are suitable candidate products for which an Adaptive Pathways approach could be to the benefit of all and in particular patients," Jones said. "Alongside initiatives working towards co-operation on HTA assessment, and PRIME (to name just a few), the issues of patient access and unmet medical need remain in focus at an EU level."

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